U.S. Pat. No. 5,883,087, “Androstane steroids as neurochemical initiators of change in human hypothalamic function and related pharmaceutical compositions and methods”, discloses a number of androstanes as vomeropherins, i.e. compounds that act on the vomeronasal organ of a human to alter hypothalamic function, and claims a method of altering a hypothalamic function of an individual by administering to the vomeronasal organ of the individual a unit dose of up to about 100 μg of androsta-4,16-dien-3β-ol, such as administering to a woman to result in reduction of premenstrual stress. U.S. Pat. No. 5,965,552, a continuation of U.S. Pat. No. 5,883,087, claims a method of reducing anxiety by vomeronasal administration of androsta-4,16-dien-3β-ol. However, neither of these patents identify “anxiety” in any detail or disclose any data demonstrating the claimed effect.
The Diagnostic and Statistical Manual of Mental Disorders—Fourth Edition, DSM-IV-TR (Text Revision), Washington D.C., USA, 2000, is the standard diagnostic manual for mental disorders. It divides anxiety disorders into several categories and sub-categories: acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder (with or without agoraphobia), posttraumatic stress disorder, and phobias (including specific phobia and social phobia).
Social phobia, also called social anxiety disorder, is classified under DSM Code 300.23, and is characterized by:
(a) a marked and persistent fear of one or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others. The individual fears that he or she will act in a way (or show anxiety symptoms) that will be humiliating or embarrassing;(b) exposure to the feared social situation almost invariably provokes anxiety, which may take the form of a situationally bound or situationally predisposed panic attack;(c) the person recognizes that the fear is excessive or unreasonable;(d) the feared social or performance situations are avoided or else are endured with intense anxiety or distress; and(e) the avoidance, anxious anticipation, or distress in the feared social or performance situation(s) interferes significantly with the person's normal routine, occupational (academic) functioning, or social activities or relationships, or there is marked distress about having the phobia; and(g) the fear or avoidance is not substance-induced or due to a general medical condition or another mental disorder.
The onset of social phobia often occurs early in life, although in many cases individuals begin to suffer from it in adolescence or adulthood. Social phobia is reported to be the most common anxiety disorder with a 1-year prevalence of 7% to 8% and a lifetime prevalence of 13% to 14%. It is diagnosed slightly more often in women than in men. Social phobia tends to be a chronic disorder with periods of exacerbation, with a reported mean duration of illness of approximately 20 years. It is believed that there may be a genetic component to social phobia, as close relatives of sufferers from social phobia are at higher risk than the general population. Given the high degree of burden of illness in social phobia, its treatment has become a major priority.
Current treatments for social phobia include both psychosocial and pharmacologic measures. Two important psychosocial treatments are exposure therapy and cognitive behavioral therapy, while pharmacological measures vary widely and are of two types: chronic treatments and acute treatments.
Chronic treatments for social phobia are treatments that are administered chronically, whether or not the sufferer from social phobia is about to experience or is experiencing a social or performance situation.
These treatments generally involve the administration of the drugs that are commonly used for generalized anxiety disorder or panic disorder, such as monoamine oxidase inhibitors (MAOs, e.g., phenelzine, tranylcypromine, seligiline and pergolide) and tricyclic antidepressants (e.g. nortriptyline and amitriptyline), and, more recently, selective serotonin reuptake inhibitors (SSRIs, e.g., fluoxetine and paroxetine) and serotonin-norepinephrine reuptake inhibitors (SNRIs, e.g. venlafaxine and nefazodone).
While these treatments are reasonably effective in preventing the anxiety/panic of social phobia when the sufferer experiences a social or performance situation, they have at least three significant drawbacks.
The first is that they have a very slow onset of action. Each of these drugs requires a period of several weeks before becoming efficacious, although once this initial period is passed, they remain effective with chronic administration. Thus these drugs cannot be used to provide rapid relief when a sufferer from social phobia encounters a social or performance situation.
The second is that their use is frequently accompanied by significant undesirable side effects. For example, MAOIs are associated with postural hypotension, sustained mild elevation of diastolic blood pressure, reactions to certain foodstuffs (e.g. cheese and red wine); tricyclics are associated with cardiac toxicity, orthostatic hypotension, dizziness, tachycardia, palpitations, blurred vision, dry mouth, urinary retention and prostate hypertrophy; and SSRIs and SNRIs are frequently associated with sexual dysfunction, headaches and nausea. Therefore, the efficacy from these drug therapies must be always be weighed carefully against the potential adverse effects of the drug.
The third is that that there is not available evidence through controlled clinical research showing that continuation drug therapy or maintenance drug therapy with the above mentioned pharmacological treatments is effective in preventing relapse or recurrences.
Also, these chronic treatments may well be also unsatisfactory to sufferers whose social phobia is not severe, either because they have a higher threshold for the onset of social phobia anxiety/panic in response to a social or performance situation or because their level of anxiety/panic when a social or performance situation is experienced is lower.
Acute treatments for social phobia are treatments that are administered when the sufferer is about to experience or is already experiencing a social or performance situation.
Beta-blockers such as seligiline and pergolide are used as an acute treatment for social phobia, but are only effective when dosed sufficiently in advance of the triggering event that the drug (which is administered orally) is absorbed from the GI tract, enters the circulatory system, crosses the blood-brain barrier, and binds to receptors in the brain. Thus, they must be administered at least 30 to 60 minutes before the sufferer experiences the triggering event. They are therefore of only limited value because a sufferer from social phobia may not be able to predict the occurrence of a triggering event and prepare for it by administering the beta-blocker; and their use is frequently accompanied by undesirable side effects such as postural hypotension, sustained mild elevation of diastolic blood pressure and reactions to certain foods.
There are no current acute treatments for social phobia that are effective in relieving social phobia anxiety once the sufferer is already experiencing a social or performance situation.
There is therefore a need for an effective treatment for social phobia, including a treatment that can be effectively administered when a sufferer from social phobia is about to experience or is even already experiencing a social or performance situation as acute treatment, especially a treatment that can be effectively administered when the sufferer is already experiencing a social or performance situation; and especially a treatment that is not accompanied by the undesirable side effects that are associated with current treatments.